This application is for a K08 award for Ann Dennis MD, an Assistant Professor of Medicine in the Division of Infectious Diseases at the University of North Carolina, who is training to become an independent investigator in HIV transmission, epidemiology, and prevention. Despite marked advances in HIV treatment and prevention, new HIV diagnoses continue in the southeastern US where significant disparities still exist among racial minorities and men who have sex with men. Innovative methods are needed to successfully decrease incident HIV infections among these vulnerable groups. The identification of phylogenetic HIV transmission networks or clusters, which are highly related sequences from individuals with shared HIV transmission, offers unique insight into the structure of HIV transmission on a population level that cannot be obtained through contact tracing or other patient-reported history. Paired with clinical and demographic data, these transmission clusters may provide new targets to direct HIV prevention efforts for groups at highest risk for ongoing transmission. The overall research objective is to characterize local phylogenetic clusters in North Carolina and investigate the use of phylogeny in the public health setting to target future interventions. The proposed study will employ innovative methods in molecular epidemiology to reconstruct transmission clusters using large repositories of HIV pol sequences extracted from antiretroviral resistance testing sent during routine clinical care. The aims of the study are to: 1) Identify the temporal and clinical features of emerging or expanding HIV transmission clusters in a large clinical cohort of new and established HIV cases; 2) Assess the effect of higher density sampling of prevalent HIV cases on the detection of transmission clusters and characterize the statewide epidemic structure; and 3) Determine feasibility of incorporating HIV sequence analysis into routine HIV surveillance in a circumscribed geographic area. Dr. Dennis's mentoring team will consist of primary mentor Joseph Eron, MD, Professor of Medicine at UNC with over 20 years of experience in HIV clinical and epidemiologic research. Two co-mentors will offer complementary areas of expertise in HIV epidemiology and phylogenetics: William Miller, MD, PhD, MPH, Associate Professor of Epidemiology and Medicine at UNC whose research focuses on HIV epidemiology; and Stephane Hue, PhD, virologist at University College London, an internationally recognized expert in HIV phylogenetics and UNC collaborator since 2010. Dr. Dennis' training plan links to the proposed research aims: establish a solid foundation in HIV epidemiology including surveillance and outbreak investigation; expand skills in phylogenetic analyses integrating time- scaled and geographic data; and explore ethical issues surrounding phylogenetics in HIV prevention. Training will be accomplished through a combination of didactic courses, workshops, and practicums. These training and research activities will allow Dr. Dennis to mature into an independent investigator and provide a basis for an R01 to implement real-time phylogeny to direct prevention interventions and track trends in HIV incidence.